Females generally have a stronger immune response than males, which is likely responsible for their increased incidence of autoimmune disease. This gender dimorphism can now be studied effectively using a murine model of relapsing experimental autoimmune encephalomyelitis (R-EAE), which has many similarities with the human demyelinating disease multiple sclerosis (MS). R-EAE in the SJL mouse is characterized clinically by relapses and remissions of neurological dysfunction, and is mediated by CD4+ Th1 cells directed at myelin antigens, predominantly the 139-151 peptide of proteolipid protein (PLP 139-151). The investigators have recently described an important gender difference in susceptibility to R-EAE. Although the initial clinical episode of EAE was similar in male and female mice, the males recovered almost completely whereas the females developed severe paralytic relapses. This clinical difference was reflected by a decreased response to PLP 139-151, and a switch in the T-helper cytokine profile in recovered males. Of critical importance, orchidectomy abrogated resistance and induced clinical relapses in males. These findings imply that the character of the immune response and susceptibility to relapses are strongly influenced by gonadal steroid hormones, and it is the investigators' goal in this application to define the mechanisms by which sex hormones influence the disease course of R-EAE. They, thus, propose to 1) determine if altered hormone levels (induced by castration or hormone replacement) modify the course of R-EAE and immunity to PLP 139-151; 2) identify hormonally induced changes in encephalitogenic and/or regulatory cells; and 3) evaluate direct effects of gonadal steroid hormones on immune effector cells.